Citrate-related symptoms, due to decreased ionized calcium (iCa) levels, are common during plateletpheresis. The role of prophylactic oral calcium administration in preventing such symptoms has not been critically evaluated. We performed a randomized, placebo-controlled, double-blind study of the efficacy of prophylactic oral calcium administration in mitigating symptoms of citrate toxicity during plateletpheresis. Twenty-three donors underwent four 90-minute platelet-pheresis procedures each; performed every 4 to 8 weeks at constant citrate infusion rates of 1.5 mg/kg/min, using a Baxter CS-3000 device. Donors randomly received either calcium carbonate 1 or 2 gm (1C or 2C, supplied as TUMS 500 mg/tablet) or an identical-appearing placebo (1P or 2P) 30 minutes before donation. Symptoms were scored as 1 (barely noticeable), 2 (irritating), 3 (uncomfortable), or 4 (unbearable). Procedure flow rates were decreased by 16 percent for symptoms greater than or equal to grade 2 and stopped for grade 4 symptoms. Serum samples were analyzed before and after tablet ingestion, every 30 minutes during donation, and the day after donation. Urinary solutes were measured in both spot samples and 24-hour collections pre- and post-donation. Investigators were blinded until completion of all four procedures. Concentrations are in mmol/L, statistics are by 2-tailed McNemar and paired t-tests. At 90 minutes, serum total calcium (tCa) was higher after either oral calcium dose compared to placebo, 2.24/2.13 (2C/2P, p less than 0.000003) and 2.20/2.13 (1C/1P, p less than 0.0004), while the absolute and percent decrease in iCa was lower after 2 gm (2C/2P: 0.90/0.85 and 29/33 percent, p less than 0.0006) but not after 1 gm (1C/1P: 0.86/0.85 and 31/33 percent, p greater than 0.27) of oral calcium. Circumoral paresthesias improved significantly with the 2 gm oral calcium dose compared to placebo (unchanged in nine, better in 13, worse in two donors, p less than 0.008), with a trend toward decreased overall symptoms (6/8 grade 2, 4/6 grade 3, and 0/2 grade 4) after either dose of calcium compared to placebo (C/P). Serum citrate levels were equivalent in all groups. Post- versus pre-donation urinary spot calcium excretion increased markedly (greater than seven-fold) in all groups. Laboratory data revealed a trend toward a sustained calcium-avid state in donations without oral calcium: day-after parathyroid hormone (PTH) increased (17 to 34 percent) and urinary calcium excretion decreased (4 to 7 percent) after placebo (1P to 2P), while day-after PTH decreased (5 to 13 percent) and calcium excretion increased (13 to 23 percent) after oral calcium (1C-2C). These data show that ingestion of a commercially available preparation of oral calcium carbonate 30 minutes prior to plateletpheresis reduces donor symptoms and increases serum Ca levels. The more pronounced effect of the 2 gm versus 1 gm dose suggests that higher doses might show even greater efficacy. The changes in PTH response and calcium excretion over 24 hours suggest that future studies of bone metabolism and calcium balance in frequent platelet donors should be initiated.